Abstract (Description) The prevalence of type 2 diabetes and nonalcoholic fatty liver disease continues to rise, devastating millions of American life. In the past funding period, we discovered that genetic deletion of SH2B1 causes obesity, type 2 diabetes, hyperlipidemia and NAFLD in mice. Importantly, SH2B1 is similarly produced in humans, suggesting that the dysfunction of human SH2B1 is also a primary risk factor for hyperlipidemia, nonalcoholic fatty liver disease, and type 2 diabetes. We discovered that central SH2B1, mainly in the brain, controls body weight, whereas peripheral SH2B1 controls fuel substrate metabolism (e.g. glucose and lipids). In the current proposal, we will identify the metabolic functions of SH2B1 in fat and liver, two essential tissues that control the levels of glucose and lipids in the circulation. We have generated genetically-modified mice which do not produce SH2B1 only in fat or in the liver, respectively. We will determine whether lack of SH2B1 in fat or in the liver disrupts normal functions of these two organs, thereby causing, or predisposing to, nonalcoholic fatty liver disease and type 2 diabetes. We will identify the underlying molecular mechanisms. The findings in this project will provide guidance for the development of new therapies for the treatment of nonalcoholic fatty liver disease and type 2 diabetes. We have four specific Aims: Aim 1. Determine whether SH2B1 mediates insulin- stimulated glucose uptake in adipocytes by promoting GLUT4 trafficking. Aim 2. Determine whether adipose SH2B1 regulates systemic insulin sensitivity and energy substrate metabolism in mice. Aim. 3. Determine whether SH2B1 cell-autonomously regulates the gluconeogenic, lipogenic and -oxidation programs in hepatocytes. Aim 4. Determine whether hepatic SH2B1 regulates hepatic metabolism, systemic insulin sensitivity and energy substrate homeostasis in mice. . Public Health Relevance Statement (Narrative attachment) The prevalence of type 2 diabetes and nonalcoholic fatty liver disease continues to rise, devastating millions of American life. In the past funding period, we discovered that genetic deletion of SH2B1 causes obesity, type 2 diabetes, hyperlipidemia and nonalcoholic fatty liver disease in mice. We further demonstrated that brain SH2B1 controls body weight, whereas SH2B1 in peripheral tissues controls fuel substrate metabolism (e.g. glucose and lipids). Importantly, SH2B1 is also produced in humans and may perform similar functions. In this project, we will identify the metabolic functions of SH2B1 in fat and the liver, two essential tissues that control levels of glucose and lipids in the circulation. We will also determine whether lack of SH2B1 in fat or in the liver causes hyperlipidemia, nonalcoholic fatty liver disease and type 2 diabetes in mice. The findings in this project will provide guidance for the development of new therapies for the treatment of hyperlipidemia, nonalcoholic fatty liver disease and type 2 diabetes.